1. Field of the Invention
The present invention relates to peptides having the activities of epidermal growth factor and their uses.
2. Description of the Related Art
Human epidermal growth factor consisting of 53 amino acid residues was first isolated by Dr. Stanley Cohen from mouse submandibular gland, and was elucidated to accelerate eyelid opening in the precocious new born mice (Cohen, S. (1962) J. Biol. Chem, 237, 1555-1562). Dr. Stanly Cohen was awarded Novel medical prize in 1986 for EGF studies. EGF, a polypeptide containing 3 disulfide bonds (Savage, C. t., Jr. et al., (1973) J. Biol. Chem. 248, 7669-7672; Savage, C. R., Jr. et al., (1972) J. Biol. Chem. 247, 7612-7621), triggers a signal transduction cascade via EGF receptor to induce growth and division of mammalian cells, particularly epithelium and skin cells, thereby promoting growth of epithelial cells (Sporn, M. B. et al., (1985) Nature (London) 313, 745-747; Sporn M. B. et al., (1980) N. Engl. J. Med. 303, 878-880). Furthermore, EGF has been reported to play a pivotal role in molecular regulation of wound healing (Buckley, A. et al., (1985) Proc. Natl. Acad. Sci. USA. 82, 7340-7344).
EGF is present at high level in various body fluids such as saliva, urine, milk, tear and blood. Upon being wounded, EGF provided to injured sites through blood stream contributes to wound healing without scar. In addition, EGF together with FSH (follicle stimulation hormone) is involved in maturation of fertilized egg in the uterus and EGF is responsible for regeneration of the cornea that is liable to degeneration due to the absence of blood vessels. Moreover, EFG plays a very important role in skin regeneration through the following various actions: promoting proliferation of epithelia and endothelia cells; promoting proliferation of fibroblasts to synthesize collagen in dermis; promoting angiogenesis at wounded sites; inducing secretion of factors implicated in regeneration; and promoting biosynthesis of fibronectin to form networking of skin tissues.
Human body responds to the occurrence of wounds and supplies EGF to injured tissues for healing. However, where the supply of EFG is not sufficient in body, exogenous EGF should be provided to go back to normal and healthy states. In this regard, EGF is considered to have a large multitude of applications. For example, EGF may be applied to diabetic foot ulcer, burn, wound, cornea injury, laparotomy, cosmetic peeling and skin aging. Besides epithelial cell proliferative potencies, hEGF has been suggested to be useful in treatment of gastric ulcer by preventing secretion of gastric acid (Gregory, H., (1985) J. Cell Sci. Suppl. 3, 11-17).
hEGF in urine was purified and characterized in 1975 by Dr. Srarkey; thereafter much efforts have been made to prepare hEGF in much higher yield and amount (Starkey, R. H. et al., (1975) Science 189, 800; Cohen. S. et al., (1975) Proc. Natl. Acad. Sci. USA 72, 1317). Several laboratories have reported a successful cloning of the hEGF gene (Smith, J. et al., (1982) Nucleic Acids Res. 10, 4467-4482; Urdea, M. S. et al., (1983) Proc. Natl. Acad. Sci. USA 80, 7461-7465; Oka, T, et al., (1985) Proc. Natl. Acad. Sci. USA 82, 7212-7216). However, hEGF prepared by the genetic recombinant technologies has not yet been produced in a large amount and high activities useful in industry fields.
Most of polypeptide growth factors present in blood and tissues have in vivo half life as short as several minutes. Likely, EGF shows poor structural stability. In addition, since EGF is biologically unstable and physiochemically heterogeneous, it is likely to show reduced treatment efficacies. Its skin permeation is far poor.
Accordingly, there remain needs to develop novel substances having improved stability and skin permeation potency as well as possessing EGF inherent activities.
Throughout this application, various patents and publications are referenced and citations are provided in parentheses. The disclosure of these patents and publications in their entities are hereby incorporated by references into this application in order to more fully describe this invention and the state of the art to which this invention pertains.